Introduction
Hemophilia B is characterized by a deficiency in clotting factor IX due to mutations in the F9 gene, impairing coagulation and increasing bleeding risk. Predominantly affecting males, hemophilia B can be classified as mild (factor IX activity >5% and <40% of normal levels), moderate (1%-5%), or severe (<1%). The primary clinical manifestation is bleeding, most commonly musculoskeletal bleeding, which can lead to severe joint disease and significantly impact the quality of life.Management of hemophilia B involves prophylactic intravenous injections of factor IX replacement therapy. However, this treatment is associated with limitations such as high treatment burden (potentially leading to non-compliance), development of inhibitors to infused factors, low trough levels of factor IX (potentially causing breakthrough bleeds and increased risk of joint disease), and individual dose variability. Extended half-life factor IX concentrates have improved bleeding protection and treatment burden. Adeno-associated virus (AAV)-based factor IX gene therapy offers a promising approach to overcoming these limitations. Recently, Lancet Haematology published the long-term follow-up results of the HOPE-B trial, which explored the efficacy and safety of the gene therapy etranacogene dezaparvovec in patients with hemophilia B.
Background
Gene therapy can provide sustained prophylactic levels of factor IX, and the use of AAV vectors has been shown to be feasible. Etranacogene dezaparvovec is the first approved gene therapy for hemophilia B, demonstrating superior bleeding protection compared to continuous prophylactic factor IX treatment in a phase 3 trial. Here, we report the 24-month follow-up efficacy and safety data from this trial to assess the long-term effects of etranacogene dezaparvovec in patients with hemophilia B.
Methods
The HOPE-B (Health Outcomes with Padua Gene; Evaluation in Haemophilia B) trial is a phase 3, open-label, single-dose, multicenter trial that enrolled male patients aged 18 and older with genetically confirmed hemophilia B, classified as severe (plasma factor IX activity level <1%) or moderately severe (plasma factor IX activity level ≥1% and ≤2%) with a severe bleeding phenotype, who were on stable continuous prophylactic factor IX treatment. Patients received a single intravenous infusion of etranacogene dezaparvovec (2×10^13 gc/kg). The primary endpoint was the non-inferiority of the annualized bleeding rate (ABR) during stable factor IX expression (defined as 7-18 months post-treatment) compared to a lead-in period of at least six months during which patients received their regular continuous factor IX prophylaxis. This endpoint was updated to 24 months post-treatment. Additional analyses included adjusted ABR, factor IX activity, factor IX usage, and safety assessments at 24 months post-treatment. Data analysis was performed on the full analysis set (FAS), which included 54 patients who received at least a partial dose of the gene therapy.
Results
The study began on June 27, 2018, with data cut-off on April 21, 2022. Patients were treated between January 2019 and March 2020. Fifty-four adult males (40 Caucasian, 2 Asian, 1 Black or African American, 11 other or missing) received a single intravenous infusion of etranacogene dezaparvovec and were followed for a median of 26.51 months (IQR 24.54–27.99) after a lead-in period of 7.13 months (6.51–7.82). Updated analyses from 7 to 24 months post-gene therapy compared to the lead-in period showed a significant reduction in the adjusted mean ABR for all bleeds from 4.18 to 1.51 (P=0.0002) and for treated bleeds from 3.65 to 0.99 (P=0.0001). During the lead-in period, 26% (14/54) of patients experienced no bleeds, increasing to 67% (36/54) during the first 0-6 months post-gene therapy and remaining stable over the following 24 months.
At 24 months post-gene therapy, one patient (2%) had a single factor IX activity level below 5%, while 18 patients (33%) had factor IX activity above 40% (non-hemophilic range), with an average factor IX activity of 36.7% (SD 19.0%). Of the 54 patients, 52 (96%) expressed endogenous factor IX and did not require factor IX prophylaxis for 24 months post-treatment. No new safety issues or treatment-related serious adverse events or deaths were observed. The most common treatment-related adverse events were elevated alanine aminotransferase [9/54 (17%)], headache [8/54 (15%)], influenza-like illness [7/54 (13%)], and elevated aspartate aminotransferase [5/54 (9%)].
Conclusion
This ongoing phase 3 trial in hemophilia B patients demonstrates that, at 18 months post-gene therapy, AAV5-based factor IX gene therapy expressing the Padua factor IX variant, etranacogene dezaparvovec, significantly reduces bleeding episodes, provides durable increases in factor IX activity, and reduces the need for factor IX replacement. The trial met its primary endpoint, showing non-inferiority (and as a secondary endpoint, superiority) of etranacogene dezaparvovec in reducing adjusted ABR compared to conventional factor IX prophylaxis.
References:
Coppens M, Pipe SW, Miesbach W, et al. Etranacogene dezaparvovec gene therapy for haemophilia B (HOPE-B): 24-month post-hoc efficacy and safety data from a single-arm, multicentre, phase 3 trial. Lancet Haematol. 2024 Apr;11(4
